Process for the preparation of olanzapine form 1 useful as antipsychotic drug

ABSTRACT

This invention provides an improved process for the preparation of Olanzapine Form (I). Olanzapine, which is 2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazapine. More specially, the invention provides insitu improved process for the direct preparation of crystalline form of Olanzapine Form (I). The present invention also provides high pure Olanzapine Form I with single individual impurity less than 0.1% by HPLC.

FIELD OF THE INVENTION

This invention provides an improved process for the preparation ofOlanzapine Form I. Olanzapine Form I, which is2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazapineForm-I. Olanzapine Form I, has the formula I given below. Morespecially, the invention provides an improved process for the directpreparation of crystalline form of Olanzapine Form-I.

Olanzapine Form I of the Formula I is a pharmaceutical compound usefulas a typical antipsychotic drug.

BACK GROUND OF THE INVENTION/PRIOR ART

The Olanzapine was first disclosed in U.S. Pat. No. 5,229,382. Theprocess disclosed in the said patent includes, condensing propanaldehydewith malanonitrile and sulphur in the presence of N,N-Dimethylformamideand triethylamine to give 2-amino-5-methyl thiophene-3-carbonitrile,which on condensation with 2-fluoronitro benzene gave 2-(2-nitroanilino)-5-methyl thiophene-3-carbonitrile, which on reduction andcyclization with stannous chloride gave4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride. The4-Amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepine hydrochloride saltwas condensed with N-Methylpiperazine in toluene and dimethyl sulphoxideto give Olanzapine which on crystallization in Acetonitrile to giveOlanzapine (Pure).

The crystal form of Olanzapine has disclosed in the U.S. Pat. No.5,736,541. As described in U.S. Pat. No. 5,736,541, the synthesis ofOlanzapine according to the methods described in U.S. Pat. No. 5,229,382produces a metastable, dull colored product referred to in the 5, 736,541 Patent as Form-I and not well suited for commercial use inpharmaceutical formulations.

The U.S. Pat. No. 5,736,541 discloses and claims a more stablepolymorphic form of Olanzapine, designated as Form-II, a method toproduce Form-II Olanzapine and pharmaceutical compositions containingForm-II.

Olanzapine. Form-I and Form-II are characterized in the U.S. Pat. No.5,736,541 by powder X-ray diffraction. The inter planar spacings(d-spacings) and typical relative intensities (I/I₁) are reported.

As per the U.S. Pat. No. 5,736,541, a typical example of an X-raydiffraction pattern for Olanzapine Form I and Form II is as followswherein d represents the inter planar spacing and I/I₁ reports thetypical relative intensities. Olanzapine Form-I Olanzapine Form-II dI/I₁ d I/I₁ 9.9463 100.00 10.2689 100.00 8.5579 15.18 8.577 7.96 8.24451.96 7.4721 1.41 6.8862 14.73 7.125 6.50 6.3787 4.25 6.1459 3.12 6.24395.21 6.071 5.12 5.5895 1.10 5.4849 0.52 5.3055 0.95 5.2181 6.86 4.98156.14 5.1251 2.47 4.8333 68.37 4.9874 7.41 4.7255 21.88 4.7665 4.034.6286 3.82 4.7158 6.80 4.533 17.83 4.4787 14.72 4.4624 5.02 4.3307 1.484.2915 9.19 4.2294 23.19 4.2346 18.88 4.141 11.28 4.0855 17.29 3.98739.01 3.8254 6.49 3.7206 14.04 3.7489 10.64 3.5645 2.27 3.6983 14.653.5366 4.85 3.5817 3.04 3.3828 3.47 3.5064 9.23 3.2516 1.25 3.3392 4.673.134 0.81 3.2806 1.96 3.0848 0.45 3.2138 2.52 3.0638 1.34 3.1118 4.813.0111 3.51 3.0507 1.96 2.8739 0.79 2.948 2.40 2.8102 1.47 2.8172 2.892.7217 0.20 2.7589 2.27 2.6432 1.26 2.6597 1.86 2.6007 0.77 2.6336 1.102.5956 1.73

U.S. Pat. No. 5,703,232 claims lower alcohol solvates of Olanzapinereferred in this patent as Form-I and methods for their preparation. Thepolymorph designated as Form I in this patent has the samecharacteristic inter planar spacing by X-ray diffraction as Form IIdisclosed in the above mentioned U.S. Pat. No. 5,736,541 and shouldtherefore be considered as Form II. In the U.S. Pat. No. 5,703,232 theForm prepared has the same characteristic inter planar spacing by X-raydiffraction as the polymorph designated as Form-II in the U.S. Pat. No.5,736,541 and therefore should thus be considered same polymorph.

U.S. Pat. No. 5,637,584 provides a methylene chloride crystallinesolvate of2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine(Olanzapine) and also provides a process for preparing anhydrous Form Iusing a methylene chloride solvate comprising drying such methylenechloride solvate and crystallizing the dried material in a solvateselected from the group consisting of aromatic hydrocarbons, C₃-C₉ketones, C₃-C₉ branched alcohols, C₃-C₉ esters, C₃-C₉ hydrocarbons,C₃-C₉ ethers and cyclic ethers in the presence of Form I2-methyl-4-(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine.

U.S. Pat. No. 3,631,250 discloses a compound selected from the groupconsisting of a methanol, ethanol, 1-propanol crystalline solvates of2-methyl-4(4-methyl-1-piperazinyl)-10H-thieno[2,3-b][1,5]benzodiazepine(Olanzapine) and provides a process for preparing anhydrous Form Icomprising contesting a lower alcohol solvate with a solvent selectedfrom the group consisting of ethyl acetate, acetone, 2-propanol,t-butanol, tetrahydrofuran, and toluene and also provides a new methodfor preparing a lower alcohol solvate of Olanzapine.

WO Patent WO 02/18390A1 describes a method for the preparation ofhydrates of Olanzapine and its conversion into a pure crystalline formof Olanzapine Form-I and also describes a method of convertingOlanzapine Form-II to From-I using methylene chloride as a solvent.

OBJECTIVE OF THE PRESENT INVENTION

The main objective of the present invention is to provide an improved,direct and simple process for the preparation of Olanzapine Form I,which is a typical antipsychotic drug overcoming the disadvantages ofthe prior art.

Another objective of the present invention is to provide an improvedprocess for the preparation of Olanzapine Form I by insitu process.

According to the present invention, there is provided an improvedprocess for the preparation of Olanzapine Form I which comprises:

-   i) Refluxing a mixture of    4-Amino-2-methyl-1H-thieno[2,3-b][1,5]benzo diazepine hydrochloride,    N-methyl piperazine, dimethyl sulphoxide and toluene under inert    atmosphere for a period in the range of 5-25 hours at a temperature    in the range of 110-130° C., preferably in the range of 122-125° C.-   ii) Cooling the resulting reaction mixture to a temperature in the    range of 20-90° C. iii) Adding demineralized water (DM water) to the    cooled mixture.-   iv) Cooling the resulting mixture to a temperature in the range of    −10 to 30° C. preferably 0-5° C. and stirring for a period in the    range of 2-10 hours.-   v) Filtering the mixture and sucking dry for a period in the range    of 0.5-2 hours.-   vi) Slurring the resulting wet cake with DM water at a temperature    in the range of 50-90° C. for a period in the range of 20 min to 3    hours.-   vii) Filtering the material and sucking dry for a period in the    range of 0.5 to 2 hours.-   viii) Repeating the steps (vi) to (vii) till the traces of dimethyl    sulphoxide and its odour are removed-   ix) Dissolving the resulting wet cake in a chlorinated solvent    preferably methylene chloride at a temperature in the range of    25-30° C.-   x) Separating the aqueous layer, if any.-   xi) Stirring the organic layer i.e. methylene chloride layer with    anhydrous sodium sulfate or anhydrous magnesium sulfate for a period    in the range of 20 min. to 2 hours.-   xii) Filtering and washing with methylene chloride.-   xiii) Repeating the steps (xi) & (xii) till the moisture content is    less than 0.1% drying the methylene chloride layer repeatedly with    anhydrous magnesium sulfate upto the moisture content below 0.1% at    25-30° C. is necessary.-   xiv) Purging dry ammonia gas in methylene chloride layer of    step (xiii) upto saturation at a temperature in the range of    25-30° C. in the presence of the anhydrous magnesium sulfate for    getting the consistent polymorphic form of Olanzapine Form I.-   xv) Removing the magnesium sulphate salts from the reaction mixture    and washing the salts with methylene chloride.-   xvi) Refluxing the methylene chloride layer for a period in the    range of 30 min to 2 hours.-   xvii) Concentrating the reaction mixture under vacuum (600-650    mm/Hg) upto product isolation takes place and distilling the    methylene chloride under vacuum-   xviii) Cooling the reaction mixture to a temperature in the range of    −10 to 25° C. preferably 0-2° C.-   xix) Stirring the material for a period in the range of 30 min. to 5    hours preferably 1-2 hours at a temperature in the range of 0-5° C.-   xx) Filtering the material and washing with chilled methylene    chloride-   xxi) Air drying the material at a temperature in the range of    25-30° C. for a period in the range of 10-15 hours and-   xxii) Vacuum drying the product with continuously maintaining a    vacuum (600-650 mm/Hg) at a temperature in the range of 60-70° C.    for a period in the range of 12-72 hours without breaking the vacuum    to avoid the impurity formation.

In a preferred embodiment of the invention, in the step (i), therefluxing may be effected preferably by 15-20 hours and at a temperaturepreferably in the range of 110-130° C., more preferably in the range of122-125° C.

In the step (vi) the stirring may be done preferably at a temperature inthe range of 60-65° C. preferably for a period in the range of 20 min to3 hours, more preferably for 45 min. to 2 hours.

The traces of dimethyl sulphoxide and its odour may be removed in step(viii) by repeating the slurry of wet cake in water at 50-90° C. for 3to 4 times is necessary. If the dimethyl sulfoxide odour is not removedtotally, it will lead to failure in the formation of Olanzapine Form I.

The moisture of Methylene chloride layer may be removed in step No(xiii) by repeating Magnesium sulphate treatment, till moisture contentof methylene chloride layer is below 0.1%. If moisture content ofmethylene chloride layer is more than 0.1%, it results the failure ofthe formation of Olanzapine Form I.

Distillation of Methylene chloride under vacuum in step No. (xvii) alsohave a key role for impurity profile while preparation of OlanzapineForm I. Impurity formation is observed when the methylene chloride layeris distilled atmospherically at 45-50° C., whereas methylene chloride isdistilled under vacuum (600-650 mm.Hg) below 30° C. gave HPLC purity99.92% with single individual impurity less than 0.1%

The details of the invention are given in the Examples given below whichare provided solely to illustrate the present invention, therefore theyshould not be construed to limit the scope of the invention. Many otherspecific embodiments of the present invention which will be obvious andapparent to one skilled in the art from the foregoing disclosure arealso fall with in the scope of the present invention.

EXAMPLE 1

A mixture of 4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepinehydrochloride (100 g), N-Methyl piperazine (312.76 g), dimethylsulfoxide (460 ml) and toluene (460 ml) were heated to reflux. Thereaction mixture was maintained at reflux for 20 hours. Completion ofthe reaction was monitored by Thin layer chromatography (TLC) and thencooled to 40-50° C. Water (460 ml) was added to the reaction mixture andfurther cooled to 0-5° C. The reaction mixture was maintained at 0-5° C.for 2 hours and filtered. Yield: 127 g (wet). Water (600 ml) & wetmaterial were stirred at 60-65° C. for 45 min. and filtered. This wasrepeated three to four times to remove the traces of dimethyl sulfoxideand its odour. Yield: 119 g (wet). Wet material was dissolved inmethylene chloride (3000 ml) and water was separated. The methylenechloride (organic) layer was dried with anhydrous magnesium sulfaterepeatedly (100 g each time) upto moisture content of organic layer wasbelow 0.1%. Dry ammonia gas was purged into the organic layer whilestirring with anhydrous magnesium sulfate (50 g) at 25-30° C. uptosaturation. The magnesium sulfate salts were filtered and washed withmethylene chloride (100 ml). The organic layers were mixed and refluxedfor 30 min. The organic layer was concentrated under vacuum (600-650mm/Hg) upto product isolation was started. The reaction mixture wascooled to 0-5° C. and maintained for 1 hr. at 0-5° C. Product wasfiltered and washed with chilled methylene chloride (50 ml) Yield: 93.0g. The product was air dried for 12 hours. Yield: 72.0 g. The air driedproduct was further dried under vacuum (600-650 mm/Hg) at 60-70° C. for48 hours continuously gave 99.92% pure Olanzapine Form 1. Yield: 61.5 g.The inter planer spacing (d-spacings) and typical relative intensities(I/I₁) of powder X-ray diffraction were as follows. d-value I/I₁ 9.92608100.0 8.52807 29.5 8.19986 18.2 6.87492 12.9 6.36322 5.6 5.91157 4.55.58243 3.0 4.97055 7.2 4.82631 80.0 4.73300 32.2 4.61640 24.8 4.5278134.8 4.23463 19.4 4.08680 34.0 3.82153 8.5 3.75505 21.1 3.69123 40.03.57709 7.1 3.50332 9.4 3.34467 7.8 3.23650 6.1 3.10616 7.6 3.03905 3.52.88339 2.6 2.82043 3.9 2.75676 5.8 2.59189 5.8 2.46045 6.6 2.38299 4.32.32966 5.5 2.12544 3.9 2.05751 2.6

EXAMPLE 2

A mixture of 4-Amino-2-methyl-10H-thieno-[2,3-b][1,5]benzodiazepinehydrochloride (25 g), N-Methyl piperazine (78.19 g), dimethyl sulfoxide(115 ml) and toluene. (115 ml) were heated to reflux. The reactionmixture was maintained at reflux for 20 hours completion of the reactionwas monitored by Thin layer chromatography (TLC) and then cooled to40-50° C. Water (115 ml) was added to the reaction mixture and furthercooled to 0-5° C. The reaction mixture was maintained at 0-5° C. for 2hours and filtered. Yield: 32.0 g (wet). Wet material was charged 150 mlwater and stirred at 60-65° C. for 45 min. followed by filtration. Wetmaterial and water (150 ml) were stirred at 60-65° C. and repeated threeto four times to remove the traces of dimethyl sulfoxide and its odour.Yield: 31.3 g (wet). Wet material was dissolved in chloroform (750 ml)and water was separated. The chloroform (organic) layer was dried overanhydrous magnesium sulfate repeatedly (25 g each time) till themoisture content of organic layer was below 0.1%. Dry ammonia gas waspurged into the organic layer while stirring with anhydrous magnesiumsulfate (12.5 g) at 25-30° C. upto saturation. The magnesium sulfatesalts were filtered and washed with chloroform (25 ml). The organiclayers were combined and refluxed for 30 min. The organic layer wasconcentrated under vacuum (600-650 mm/Hg) upto product isolation wasstarted. The reaction mixture was cooled to 0-5° C. and maintained for 1hour at 0-5° C. Product is filtered and washed with chilled chloroform(12.5 ml) Yield: 11.6 g (wet). The product was air dried for 12 hours.Yield: 10.0 g. The air dried product was further dried under vacuum(600-650 mm/Hg) at 60-70° C. for 48 hours continuously gave 99.50% pureOlanzapine Form I. Yield: 8.5 g. The inter planer spacing (d-spacings)and typical relative intensities (I/I₁) of powder X-ray diffraction wereas follows. d-value I/I₁ 9.84970 100.0 8.47167 6.8 8.14210 7.1 6.820064.3 6.32759 2.3 5.54555 1.7 4.95573 3.4 4.79761 25.7 4.71634 17.34.59634 10.1 4.50564 12.1 4.22111 9.8 4.07202 12.2 3.74199 8.2 3.6861612.2 3.55808 2.0 3.49212 2.7 3.23037 2.6 3.09860 3.0 2.80907 2.0 2.745701.6 2.58950 1.8 2.45437 1.9 2.32630 2.0

The aforementioned crystalline forms prepared by the process describedin the Examples 1 to 2 have been examined for their structural andanalytical data viz., powder X-ray diffraction (XRD) and Infraredabsorption spectroscopy (IR). The results obtained are discussed and therespective drawings attached (FIG. 14).

The X-ray diffraction pattern setout herein for examples 1 to 2 wereobtained using X-ray diffractrometer having a copper anode, radiationsource of wave length λ=1.5406A°. The samples were scanned between2.000° to 50.000° of 2-theta scale.

In the drawings

FIG. 1 is a characteristic X-ray powder diffraction pattern ofOlanzapine Form I obtained by the process described in the Example—1(vertical axis: Lin (counts); Horizontal axis: 2-theta scale).

FIG. 2 is a characteristic infrared as absorption spectrum in potassiumbromide of Olanzapine Form I obtained by the process described in theExample—1 (vertical axis, tramission (%); Horizontal axis: wave number(cm⁻¹)).

FIG. 3 is a characteristic X-ray powder diffraction pattern ofOlanzapine obtained by the process described in the Example—2 (verticalaxis: Lin (counts); Horizontal axis 2-theta scale).

FIG. 4 is a characteristic infrared as absorption spectrum in potassiumbromide of Olanzapine obtained by the process described in theExample—2. (vertical axis, tramission (%); Horizontal axis: wave number(cm⁻¹)).

ADVANTAGES OF THE INVENTION

-   1. The present invention is simple and insitu process for direct    preparation of Olanzapine Form I.-   2. The other advantage of the present invention is to get    consistently polymorphic form I by controlling following parameters.    -   i) Removal of dimethyl sulphoxide and its odour by repeating the        slurry of wet cake in hot water.    -   ii) Drying the methylene chloride layer repeatedly with        anhydrous magnesium sulphate upto the moisture content below        0.1% at 25-30° C.    -   iii) Purging dry ammonia gas in methylene chloride upto        saturation at 25-30° C. in the presence of the anhydrous        magnesium sulphate.-   3. The present process results in getting polymorphic Form I with    single individual impurity less than 0.1%.-   4. The process is simple, safe and can be employed for commercial    production.

1.-10. (canceled)
 11. An improved process for the in situ preparation ofOlanzapine Form I, said process comprising: (i) dissolving substantiallyDMSO-free crude olanzapine in a chlorinated solvent to form a solutionincluding olanzapine; (ii) drying the solution including olanzapine toform a substantially water-free solution including olanzapine; (iii)refluxing the substantially water-free solution including olanzapine;and (iv) concentrating the substantially water-free solution includingolanzapine at reduced pressure for sufficient time to precipitateolanzapine Form I crystals.
 12. The improved process of claim 11,wherein a process of preparing crude olanzapine comprises: (a) refluxinga mixture of 4-amino-2-methyl-10H-thieno[2,3-b][1,5]benzodiazepinehydrochloride, N-methyl piperazine, dimethylsulfoxide and toluene in aninert atmosphere at elevated temperature for a sufficient time.
 13. Theimproved process of claim 11, wherein a process of preparingsubstantially DMSO-free crude olanzapine comprises: (I) mixing a cleanaliquot of water and crude olanzapine at a temperature in a range from50° C. to 90° C. for a sufficient time; (II) separating the crudeolanzapine from the aqueous mixture; and (III) repeating (a) and (b) ntimes, wherein n is from 1 to 4, to substantially remove DMSO and yieldsubstantially DMSO-free crude olanzapine.
 14. The improved process ofclaim 13, wherein n is 3 or
 4. 15. The improved process of claim 11,wherein a process of drying the solution including olanzapine comprises:(A) removing water from the solution including olanzapine using a dryingagent to form a substantially water-free mixture including olanzapine;(B) purging dry ammonia gas in the substantially water-free mixtureincluding olanzapine; and (C) removing the drying agent from thesubstantially water-free mixture including olanzapine to form asubstantially water-free solution including olanzapine.
 16. The improvedprocess of claim 15, wherein the drying agent comprises an anhydroussulfate salt selected from the group consisting of sodium sulfate andmagnesium sulfate.
 17. The improved process of claim 11, wherein thesubstantially water-free solution including olanzapine comprises waterin a range from 0.0% to 0.1%.
 18. The improved process of claim 11,wherein the reduced pressure is in a range from 0.789 atm to 0.855 atm.19. The improved process of claim 11, wherein the chlorinated solventcomprises methylene chloride.
 20. The improved process of claim 11,further comprising: (v) separating the olanzapine Form I crystals fromthe substantially water-free solution; and (vi) drying the olanzapineForm I crystals at reduced pressure for a sufficient time.
 21. Theimproved process of claim 20, wherein the reduced pressure is in a rangefrom 0.789 atm to 0.855 atm.
 22. The improved process of claim 20,wherein the olanzapine Form I crystals are dried at temperature in arange from 60° C. to 70° C.
 23. The improved process of claim 20,wherein the sufficient time for drying the olanzapine Form I crystals isin a range from 12 hours to 72 hours.
 24. The improved process of claim20, further comprising rinsing the olanzapine Form I crystals with achlorinated solvent prior to drying said crystals.
 25. The improvedprocess of claim 24, wherein the chlorinated solvent comprises methylenechloride.